Overall - SUMMARY/ABSTRACT The overall goal of the University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma (HCC) is to improve outcomes for HCC patients and reduce the mortality rates of HCC through early intervention. HCC is the 2nd leading cause of cancer death worldwide with 854,000 new cases diagnosed globally and 810,000 deaths in 2015. The incidence of new HCC cases globally is projected to rise to 1,341,344 cases by 2035. In the United States (U.S.), while death rates declined for all cancers combined and for most cancer sites in the past 10 years, deaths from HCC increased at the highest rate of all cancer sites, and HCC incidence rates increased sharply, second only to thyroid cancer. The burden of HCC is not equally distributed throughout the U.S., the highest incidence being observed in States on the Mexico-US Border. Texas ranks second in incidence of HCC, with a 5-year rate of 11.4 cases per 100,000 compared to the nation rate of 7.6. Within Texas, Hispanics in counties bordering Mexico have the highest rates of HCC in the U.S., with 37.5 diagnosed cases per 100,000. Reflecting the rising incidence trends, the number of HCC patients seeking care at MD Anderson Cancer Center has increased every year, from 277 patients in 2013 to 580 patients in 2017, a 2-fold increase over the most recent 5 years. The relative 5-year survival rate for HCC is 16%. The poor prognosis of HCC is due to multiple factors: 1) the vast majority of HCC cases are diagnosed at an advanced stage, not amenable to curative surgical treatment (resection or liver transplantation); 2) even resected cases suffer from high rates of recurrence (up to 50% in 2 years and 70% in 5 years); 3) HCC often occurs in the context of advanced chronic liver disease, cirrhosis in particular, limiting treatment options; 4) the only FDA-approved first line systemic therapy is sorafenib which offers a 2.8 months improvement in overall survival and a dismal response rate of 2%; and 5) the recently approved second line therapy are another tyrosine kinase inhibitor regorafenib and the immunotherapy drug nivolumab, but again improvement in overall survival and response rates are very low. In this SPORE application, 3 projects together with 3 cores will: 1) evaluate the effect of checkpoint therapy in neoadjuvant and adjuvant HCC settings and determine optimal combinations with checkpoint therapeutics to enhance the anti-tumor immune response; 2) determine the prognostic significance of phosphorylated STAT3 as a biomarker for postoperative recurrence and evaluate TTI-101 (C188-9), a STAT3 inhibitor developed in-house, as a post-operative adjuvant; 3) evaluate the combination of nivolumab and TTI-101 in the treatment of patients with advanced stage HCC; 4) perform extensive screening for liver fibrosis in obese and diabetic Hispanics in South Texas, and identify non-invasive biomarkers of fibrosis stage and progression in this underserved population highly affected by non-alcoholic steatohepatitis and HCC.